The present invention relates to a method and a pharmaceutical preparation for treating pain, especially colic pain such as biliary colic pain.
Treating biliary colic pain is extremely difficult as the use of spasmogenic analgesics such as opioids is undesirable and contraindicated due to their spasmogenic action on the biliary tract particularly at the sphincter of Oddi, and thus the spasmogenic analgesics worsen the pain rather than alleviating the same.
According to Jaffe J. H., Martin W. R., Opioid analgesic and antagonists. In: Goodman A., Goodman L. S.; Gilman A. (eds) the Pharmacological Basis of Therapeutics. New York 1980; Macmillan Publishing Co.: 494-534. (Pages 504-505), therapeutic doses of spasmogenic analgesics, particularly of morphine, or codeine, and other morphine surrogates, can cause a marked increase in pressure in the biliary tract. Some patients with biliary colic pain may experience exacerbation and not relief of pain when given these drugs. Furthermore, an occasional individual complains of pain in the epigastrium or right hypochondrium after administration of morphine, probably due to duodenal or biliary tract spasm. Spasm of the biliary tract produced by morphine is evident roentgenographically as well as manometrically, and a sharp constriction becomes apparent at the lower end of the common bile duct (sphincter of Oddi). This spasm prevents emptying and thus causes the intraductal pressure to rise.
In Martindale, The Extra Pharmacopoeia. Reynolds J. E. F. (ed). 28th edition, London 1982: The Pharmaceutical Press. Pg. 1020 this spasmogenic action of the alkaloid opiates (morphine and morphinelike substances) is also pointed out.
Other therapeutic approaches have been the use of anticholinergic agents as spasmolytic substances, which have been widely employed but on an empirical basis, because there is no conclusive evidence that they are efficient.
Glucagon has been shown to be efficient in relieving biliary colic pain in several studies (see Paul F, The role of glucagon in the treatment of biliary tract pathology. In: Picazo J. (ed) Glucagon in Gastroenterology. Lancaster 1979; MTP Press: 10-120; Brandstatter G., Kratochvil P., Glukagon Bei Gallenkoliken. Therapiewoche 1979; 29:3362-3365), (see also Hard-castle J. D., Stower M. J., Foster G. E., The use of glucagon in spastic disorders of the gastrointestinal tract. In: Picazo J. (ed) Glucagon in Gastroenterology and Hepatology. Pharmacological, Clinical, and Therapeutic Implications. Lancaster 1982; MTP Press: 115-125; Stower M. J., Foster G. E., Hardcastle J. D., a trial of glucagon in the treatment of biliary tract disease. Br J. Surg 1982; 69:591-592; Grossi E., Broggini M., Quaranta M., Balestrino E., Different pharmacological approaches to the treatment of acute biliary colic. Curr Ther Res 1986; 40:876-882). However, the relief of pain is not as immediate as is desirable. The same thing applies to the results obtained with the use of prostaglandin synthesis inhibitors, i.e., diclofenac sodium (Grossi et al., ibid).
Glucagon is known to reverse the biliary spasm induced by administration of narcotics in man (Bordley J., Olson J. E., The use of glucagon in operative cholangiography. Surg Gynecol Obstet 1979; 149:583-584; Jones R. M., Fiddian-Green R., Knight P. R., Narcotic-induced choledochoduodenal sphincter spasm reversed by glucagon. Anesth Analg 1980: 59:946-947; Jones R. M., Coultas R. J., Pollard B. J., Waterland J. W., Reversal of biliary sphincter spasm with low dose Glucagon during operative cholangiography. Anaesth Intens Care 1983; 11:1174-175; McCammon R. L., Stoelting R., Madura J. A., Reversal of fentanyl induced spasm of the sphincter Oddi. Surg Gynecol Obstet 1983; 156:326-334; and Setakis N., Economou J., Ritsi N., Konidis A., Georgiadis N., Andoniou G., Effect of cimetidine, glucagon, propantheline bromide, morphine, pethidine, naloxone, ethyl alcohol on sphincter of Oddi (Abst). Gut 1990; 31: A488). McCammon et al. have demonstrated this by radio manometric methods and Carr-Locke and Gregg by endoscopic manometry. According to Carr-Locke D. L., see Glucagon and the human biliary tree. In: Picazo J. (ed) Glucagon in 1987. Gastrointestinal and Hepatobiliary Physiology, Diagnosis and Treatment. Lancaster 1987; MTP Press: 67-86 (Pages 76-79, 85), glucagon is an inhibitor of gastrointestinal motility, and glucagon would seem to have opposing effects to opiates, i.e., morphine. In his study, the spasm induced by the intravenous administration of 5 mg morphine was reversed 2 minutes after the intravenous injection of 1 mg Glucagon. This is believed to suggest that spasmogenic analgesics, particularly the opiate alkaloids and notably morphine and glucagon either share a common receptor site or share some common pathway of smooth muscle cell control perhaps through their known effects in intracellular cyclic nucleotides.
All the above evidence explains why use of spasmogenic analgesics are contraindicated for treatment of biliary colic pain. However, due to the high efficiency analgesic effects of opioides it is very desirable to have available the possibility to utilize them in relieving pain in patients suffering from biliary colic pain.